PROJECT SUMMARY/ABSTRACT It is estimated that at least 12% of the population is affected by olfactory loss. Anosmia, the loss of olfactory function, can be due to aging, prior infection, or injury, and there are currently no effective treatments. Although etiologies may vary, evidence suggests that neurogenic exhaustion, or a failure to replace or maintain the olfactory neuron population, underlies many olfactory disorders. The regulation of adult olfactory neurogenesis is, therefore, an area of active research. Building upon recent successes permitting the purification and culture of adult olfactory basal stem or progenitor cells (globose basal cells), and the identification of Polycomb complexes in subsets of olfactory cells, this proposal asks whether and how Polycomb complex-mediated epigenetic modifications influence neurogenesis and epithelial homeostasis in the olfactory epithelium. Polycomb complexes are essential epigenetic regulators during development, but their roles in olfactory maintenance and renewal have not been investigated. Using a culture model, chromosome immunoprecipitation- DNA sequencing (ChIP-seq), as well as in vivo approaches, Aim1 will test the hypothesis that Polycomb complexes regulate renewal and differentiation in the olfactory epithelium. In addition to defining epigenetic regulation in basal cells, Aim2 will test the ability of basal stem cells to be used to repair olfactory damage. This Aim will address a major translational question: can a cell-based therapy treat a sensorineural anosmia? Because regenerating host neurons interfere with the assessment of functional recovery following olfactory lesions in mice, we will employ a novel inducible anosmia mouse model, in which regenerating neurons lack cilia, for testing therapeutic potential of engrafted cells. The experiments will combine histology, electrophysiology and behavioral approaches to comprehensively evaluate basal cell engraftment into inducible anosmia hosts. Also, this model will be used to directly test the effects of altering Polycomb expression in donor cells. These studies, guided by important clinical problems lacking current treatments, will use innovative multi-pronged approaches to define previously unexplored mechanistic controls of olfactory renewal and differentiation, and will provide essential data to design cell-based therapy for sensorineural olfactory losses secondary to damage or neurogenic exhaustion, such as presbyosmia.